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Review
. 2021 Mar;66(3):674-693.
doi: 10.1007/s10620-020-06715-3. Epub 2020 Dec 8.

Bile Acid Signaling in Inflammatory Bowel Diseases (V体育ios版)

Stefano Fiorucci  1   2 , Adriana Carino  3 , Monia Baldoni  4 , Luca Santucci  5 , Emanuele Costanzi  6 , Luigina Graziosi  7 , Eleonora Distrutti  5 , Michele Biagioli  3
Affiliations
Review

"VSports手机版" Bile Acid Signaling in Inflammatory Bowel Diseases

Stefano Fiorucci et al. Dig Dis Sci. 2021 Mar.

Abstract

Bile acids are a group of chemically different steroids generated at the host/microbial interface. Indeed, while primary bile acids are the end-product of cholesterol breakdown in the host liver, secondary bile acids are the products of microbial metabolism. Primary and secondary bile acids along with their oxo derivatives have been identified as signaling molecules acting on a family of cell membrane and nuclear receptors collectively known as "bile acid-activated receptors. " Members of this group of receptors are highly expressed throughout the gastrointestinal tract and mediate the bilateral communications of the intestinal microbiota with the host immune system. The expression and function of bile acid-activated receptors FXR, GPBAR1, PXR, VDR, and RORγt are highly dependent on the structure of the intestinal microbiota and negatively regulated by intestinal inflammation. Studies from gene ablated mice have demonstrated that FXR and GPBAR1 are essential to maintain a tolerogenic phenotype in the intestine, and their ablation promotes the polarization of intestinal T cells and macrophages toward a pro-inflammatory phenotype. RORγt inhibition by oxo-bile acids is essential to constrain Th17 polarization of intestinal lymphocytes. Gene-wide association studies and functional characterizations suggest a potential role for impaired bile acid signaling in development inflammatory bowel diseases (IBD). In this review, we will focus on how bile acids and their receptors mediate communications of intestinal microbiota with the intestinal immune system, describing dynamic changes of bile acid metabolism in IBD and the potential therapeutic application of targeting bile acid signaling in these disorders. VSports手机版.

Keywords: Dysbiosis; FXR; GPBAR1; Innate immunity; Intestinal microbiota; RORγt V体育安卓版. .

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Conflict of interest statement (VSports注册入口)

Prof. Stefano Fiorucci, is listed as an inventor of some of the compounds mentioned in this paper: INT767 (Intercept Pharmaceuticals), BAR501 and BAR502 (Bar Pharmaceuticals) and has received research grants from BAR Pharamceuticals V体育ios版. The other authors do not have any conflict of interest to be disclosed.

Figures

Fig. 1
Fig. 1
Hepatic bile acid metabolism. a Bile acids are synthesized in the liver from cholesterol by two metabolic pathways known as the classical (or neutral) and the alternative (acidic) pathway. In the classical pathway, cholesterol is metabolized to 7α-hydroxycholesterol by CYP7A1 and then to CA by CYP8A1 or to CDCA by CYP27A1. On the other hand, in the acid pathway, CYP27A1 converts cholesterol into 27-hydroxycholesterol which is then metabolized by CYP7B1 into CDCA. The entero-hepatic circulation of bile acids is mediated by several bile acid transporters in the liver and intestine and regulated by the FXR/SHP and FGF19/FGFR4 pathways. After their synthesis, primary bile acids are excreted into bile through the bile salt export pump (BSEP). b After secretion in the duodenum majority of BA are transported back to the liver through the portal blood. BAs are reabsorbed in the liver by NTCP. In the hepatocyte, other transporters including MRP2 on the canalicular membrane and MRP3/MRP4, OSTα/OSTβ on the basolateral membrane are also capable of BA transport into systemic circulation. c Finally, BAs are also filtered by the glomeruli and then reabsorbed in renal tubules, again limiting their renal loss. ASBT sodium-dependent bile acid transporter, BSEP bile salt export pump, FGF15 fibroblast growth factor 15, FGF-R4 FGF receptor 4, MDR2 multidrug resistance protein 2, MRP2/3/4 multidrug resistance-associated protein 2/3/4, NTCP sodium taurocholate co-transporting polypeptide, OSTα/β organic solute transporter α/β, SHP small heterodimer partner
Fig. 2
Fig. 2
Intestinal bile acid metabolism. a The two primary bile acids, CA and CDCA, are then secreted into bile ducts and transported to the intestine and converted by the intestinal microbiota into secondary bile acids, respectively, DCA and LCA, or in the respective oxo- and di-oxo-derivatives. (b) In the gastrointestinal tract, the BAs are picked up by ASBT which transports them inside the enterocyte. BAs exit the enterocytes on the basolateral side via the IBABP/OSTα /OSTβ. Moreover, in the enterocite bile acids bind FXR which downregulates ASTB and upregulates the expression of IBABP and OSTα /OSTβ. Activation of FXR also induces the expression of SHP and the production of FGF15 which is then released into the portal circulation. In intestinal L cells, bile acids bind GPBAR1 which induces the production of GLP-1 which stimulates the secretion of insulin by the pancreas. (c) Expression levels of the GPBAR1, FXR, VDR, and RORC genes along the gastrointestinal tract extrapolated from https://www.proteinatlas.org/. Consensus Normalized eXpression (NX) levels created by combining the data from the three transcriptomics datasets (HPA, GTEx and FANTOM5) using the internal normalization pipeline. ASBT sodium-dependent bile acid transporter, FGF15 fibroblast growth factor 15, IBABP ileal bile acid-binding protein, MRP2/3 multidrug resistance-associated protein 2/3, OSTα/β organic solute transporter α/β, SHP small heterodimer partner
Fig. 3
Fig. 3
Bile acid pool in inflammatory bowel diseases (IBDs). (a) In a healthy condition, the majority of bile acids are actively reabsorbed by the enterocytes by apical transporter ASBT and are transported back to the liver in the portal blood, thus limiting BA loss through feces to 3–5% of daily secreted BAs. BAs reaching the colon are metabolized by the intestinal microbiota which transforms primary bile acids into secondary bile acids. (b) In patients with IBDs, the alterations of the intestinal epithelium reduce the reabsorption of bile acids exerted by ASBT and therefore increase the quantity of bile acids that are eliminated with the feces. Furthermore, patients with IBDs have a dysbiosis of the intestinal bacterial flora which strongly decreases the enzymatic capacity of the microbiota resulting in a lower ability to metabolize primary bile acids into secondary bile acids. ASBT sodium-dependent bile acid transporter
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